Diabetic retinopathy (DR, also referred to as diabetic retinal disease) is one of the three major complications of diabetes, the others being diabetic nephropathy and diabetic neuropathy, and is the second leading cause of blindness in adults after glaucoma in Japan. If blood glucose remains at a high level, small blood vessels in the retina are gradually damaged and then deformed or blocked. As a result of such so-called hyperglycemic microangiopathy, oxygen does not reach every corner of the retina so that the retina becomes hypoxia. As a result, new blood vessels (neovascular vessels) are formed to compensate for the lack of oxygen. However, neovascular vessels are fragile, and therefore bleeding easily occurs so that a scab-like membrane (proliferative membrane) is formed on the retina, which may be the cause of retinal detachment (proliferative diabetic retinopathy).
Diabetic retinopathy is broadly classified into three stages, simple diabetic retinopathy, preproliferative diabetic retinopathy, and proliferative diabetic retinopathy depending on the degree of progression. Even in the stage of simple diabetic retinopathy, maculopathy with macular edema or hard exudate (diabetic macular edema or diabetic maculopathy) may develop, which mainly results from increased vascular permeability. In either case, diagnosis based on ocular fundus findings is important.
It is known that diabetic macular edema develops regardless of the disease stage of diabetic retinopathy. Diabetic macular edema is a disease that is caused by accumulation of a plasma component leaked from retinal blood vessels due to increased vascular permeability in the macula and that is associated with a subjective symptom such as anorthopia or reduced visual acuity.
Simple diabetic retinopathy is sometimes improved by blood glucose control, but it is believed that in most cases, preproliferative diabetic retinopathy needs to be treated by retinal photocoagulation. When proliferative diabetic retinopathy develops so that retinal detachment or vitreous hemorrhage occurs, vitreous surgery is performed for the purpose of removing blood or grown tissue in the eye or reattaching the detached retina. However, at present, it is still not always possible to maintain good visual function.
Age-related macular degeneration (AMD) is a disease in which the macula is directly or indirectly damaged by waste products accumulated under the retinal pigment epithelium by aging. In Europe and the United States, age-related macular degeneration is the first leading cause of blindness in adults. Age-related macular degeneration is broadly classified into two types, atrophic (dry) type and exudative (wet) type. Atrophic AMD is a disease in which the retinal pigment epithelium becomes atrophic gradually so that the retina is damaged and therefore visual acuity is gradually reduced. At present, there is no known effective therapy for atrophic AMD. On the other hand, exudative AMD is a disease in which the retina is damaged by abnormal blood vessels (choroidal neovascular vessels) that extend from the choroid into the space under the retinal pigment epithelium or the space between the retina and the retinal pigment epithelium. Choroidal neovascular vessels cause accumulation of fluid (subretinal fluid) under the retina due to leakage of blood components or cause bleeding in the retina due to vascular disruption (retinal bleeding), and therefore the retina is damaged and does not properly function so that visual acuity is reduced.
There are some known therapies for exudative age-related macular degeneration. All the therapies are intended to suppress the choroidal neovascularization and regress the choroidal neovascular vessels to maintain or improve visual acuity. Examples of the known therapies for exudative age-related macular degeneration include photodynamic therapy (PDT), drug therapy, laser coagulation, and surgery. Among them, drug therapy is a therapeutic method in which a drug (VEGF inhibitor), whose action mechanism is to inhibit vascular endothelial growth factor (VEGF) considered to be largely concerned with the development of choroidal neovascularization, is injected into the vitreous body to regress choroidal neovascular vessels. However, as in the case of the treatment of diabetic retinopathy, it is still not always possible to maintain good visual acuity. Further, in the case of drug therapy, it is necessary to frequently administer the drug into the vitreous body.
Retinal neovascularization or choroidal neovascularization is largely responsible for the pathology of diabetic retinopathy or age-related macular degeneration, respectively, and therefore treatment intended to suppress or inhibit neovascularization has been tried. Treatment of age-related macular degeneration by intravitreal injection of the above-described VEGF inhibitor has already been covered by insurance in Japan, and clinical trials of the VEGF inhibitor for diabetic retinopathy are also in progress.
Further, as a target molecule different from VEGF, Rho-kinase (Rho-associated protein kinase: ROCK) has recently been received attention (Non-Patent Document 1). It is known that fasudil or Y-27632 known as a ROCK inhibitor has the effect of inhibiting VEGF-induced neovascularization (Non-Patent Documents 2 and 3). When intravitreally administered to diabetic model rats as model animals with retinal microangiopathy, fasudil has the effect of protecting endothelial cells due to suppression of adhesion of neutrophils to vascular endothelium or facilitation of the synthesis of nitrogen monoxide in endothelial cells, which suggests the potential of intravitreal administration of fasudil as a new treatment strategy for early-stage diabetic retinopathy (Non-Patent Documents 4 and 5). It is also shown that Y-27632 has the effect of suppressing retinal neovascularization when intravitreally administered to model mice with hyperoxia-induced retinopathy (Non-Patent Document 6). Some patent documents disclose that novel ROCK inhibitors can be used for treatment of retinopathy, diabetic retinopathy, macular degeneration, and the like, but in these patent documents, there is no description about the specific effect of the novel ROCK inhibitors on these diseases (Patent Documents 1 to 3).
As has been briefly described above, a drug intended to suppress chorioretinal neovascularization to treat diabetic retinopathy or age-related macular degeneration is mainly administered by intravitreal injection, but multiple injection into the human eye involves the risk of infection and imposes heavy physical, emotional, and financial burdens on patients. Therefore, development of therapy with an ophthalmic preparation has been desired.
Further, it is known that a 4-fluoro-5-cycloaminosufonyl isoquinoline derivative is effective as a therapeutic agent for asthma, a substance P antagonist, a leukotriene D4 antagonist, and a Rho-kinase inhibitor (Patent Document 3) or as a therapeutic agent for cerebrovascular disorder (Patent Document 4), but there is no report about its selective action by local administration.